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Nerve Growth Factor and Substance P Regulation in Nasal Sensory Neurons after Toluene Diisocyanate Exposure

Department of Neurobiology and Anatomy, Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences Center, School of Medicine, West Virginia University, Morgantown, West Virginia

Address correspondence to: Dr. Richard D. Dey, Department of Neurobiology and Anatomy, Robert C. Byrd Health Sciences Center, P.O. Box 9128, Morgantown, WV 26506-9128. E-mail: rdey{at}hsc.wvu.edu

Toluene diisocyanate (TDI) exposure produces rhinitis and nasal irritation, and increases the synthesis and release of substance P (SP) from airway sensory nerves. The mechanism leading to enhanced SP production following irritant inhalation remains unclear, but may involve actions of nerve growth factor (NGF). NGF binds trkA receptors located on sensory nerve terminals. Activation of trkA receptors initiates kinase-signaling cascades, which ultimately may increase SP. However, the effects of inhaled irritants on NGF release are not known. In this study, NGF levels in nasal lavages were examined following instillation of 10% TDI into both nasal cavities. NGF was significantly increased 2, 6, 12, and 24 h after TDI exposure compared with controls. The increase in NGF preceded the neuronal and mucosal increases in SP. Pretreatment with K252a, a nonselective tyrosine-kinase inhibitor, prevented the increase in SP-immunoreactivity in TG neurons and epithelial nerve fibers and the inflammatory response to TDI exposure. Because NGF binds to trkA tyrosine-kinase receptors, the NGF released during TDI exposure may mediate SP upregulation in airway sensory neurons, innervating the nasal cavity.

Abbreviations: bovine serum albumin, BSA • dimethyl sulfoxide, DMSO • ethyl acetate, EA • immunoreactivity, IR • mean gray value, MGV • nerve fiber density, NFD • nerve growth factor, NGF • phosphate-buffered saline, PBS • substance P, SP • toluene diisocyanate, TDI • trigeminal ganglia, TG

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